1. Field of the Invention
The present invention relates to techniques for drug delivery, and more specifically, it relates to the use of acoustic waves for the enhancement of drug delivery.
2. Description of Related Art
Ultrasound-enhanced drug delivery has been postulated to work through a variety of mechanisms. Most notably, ultrasound produces cavitation bubbles, which are thought to disrupt the lipid bilayer membrane of cells (Mitragotri, et al. Pharm Res 1996; 13: 411-420). This disruption can cause channels to form, which can temporarily increase a cell""s permeability to certain drug compounds. The concentration of compounds which normally have low diffusion rates into the cell can be increased. Transdermally (across the skin), it has been shown that the permeability of disordered lipid bilayers can be up to 5000-fold higher than the diffusion coefficients in normal lipid bilayers (Mitragotri 1996). Other compounds, to which the cell is usually impermeable, can also be driven into the cell through the use of ultrasound.
Extracorporeal (transdermal) application of ultrasound is inappropriate when deeper penetration of the ultrasound is required for enhanced drug delivery in remote locations. In the current transdermal method, the drug of interest is applied to the skin and ultrasound is generated through the placement of a piezoelectric transducer on the skin. This ultrasound could be focused into deeper structures, similar to ultrasound imaging transducers. However, it is difficult to assess or control dosimetry to deeper structures with this method and the ultrasound does not penetrate through gas filled organs or high density tissues such as bone. If one transducer is used, a high amount of power is necessary to generate the required ultrasound in the underlying tissues. The high power needed can cause thermal damage to the skin. An array of transducers could be used to focus onto a single point beneath the skin. However, the amount of heat and stress produced as the ultrasound waves converge, may produce damage to the underlying tissue, including those that are not intended to be treated. Local generation of ultrasound solves many of these potential problems. However, the use of traditional piezoelectric materials such as PZT induce other complications. These materials need electrical stimulation, which is undesirable to deliver inside the body. Further, the large size of the piezoelectric materials required to achieve necessary ultrasound magnitudes, forbids certain in vivo applications. The present invention, with its local generation and delivery of optically generated ultrasound, facilitates the delivery of ultrasound at required intensities into remote locations.
U.S. Pat. No. 4,767,402, issued Aug. 30, 1988, titled xe2x80x9cUltrasound Enhancement Of Transdermal Drug Deliveryxe2x80x9d is directed to a method using ultrasound for enhancing and controlling transdermal permeation of a molecule, including drugs, antigens, vitamins, inorganic and organic compounds, and various combinations of these substances, through the skin and into the circulatory system. The frequency and intensity of ultrasonic energy which is applied, the media between the ultrasonic applicator and the skin, and the length of time of exposure are determined according to the type of skin and the substance to be diffused transdermally. Levels of the diffused molecules in the blood and urine measured over a period of time are initially used to determine under what conditions adequate transfer occurs. In general, the frequency range of the ultrasound is between 20 kHz and 10 MHz, with intensities between 0 and 3 W/cm less than 2 greater than . Intensity is decreased as the frequency is decreased to prevent damage to the skin. The preferred range of frequencies is between 0.5 MHz and 1.5 MHz and the preferred range of intensities is between 2 and 4 W/cm less than 2 greater than . Exposure is for between 1 and 10 minutes for most medical uses. The ultrasound may be pulsed or continuous. However, the frequency, intensity and time of exposure are interdependent as well as a function of the molecule being diffused and the nature of the skin at the site of exposure. One way of determining the maximum limit of exposure is to measure skin temperature, decreasing or stopping the treatment when the temperature of the skin rises one to two degrees Centigrade.
In U.S. Pat. No. 5,386,837, issued Feb. 7, 1995, titled xe2x80x9cMethod For Enhancing Delivery Of Chemotherapy Employing High-Frequency Force Fieldsxe2x80x9d pulse shocks of high-frequency wave energy (e.g. RF, microwave, high-energy infra-red or laser electromagnetic wave energy or ultrasonic acoustic wave energy), rather than DC electric pulses, are employed to non-invasively produce, with minimal or, if desired, a controlled amount of temperature rise in a patient""s body tissues, force fields of an intensity sufficient to create transient pores in the plasma membranes of targeted cells, such as tumor or other diseased cells, through which chemotherapeutic agents can easily be delivered, enter and taken up by these targeted cells, even for (1) deep-seated cells (e.g., the cells of a deep-seated tumor) or (2) non-localized diseased cells (e.g., metastasized tumor cells) within a patient""s body.
U.S. Pat. No. 5,421,816, issued Jun. 6, 1995, titled xe2x80x9cUltrasonic Transdermal Drug Delivery Systemxe2x80x9d described the use of Ultrasonic energy to release a stored drug and forcibly move the drug through the skin of an organism into the blood stream. A housing (81) includes a cavity (67) defined by an assembly of ultrasonic transducers (65) and separated from the skin by a polymeric membrane (69) that stores the drug to be delivered. The ultrasonic transducer assembly includes a flat, circular ultrasonic transducer (85) that defines the top of a truncated cone and a plurality of transducer segments (87a, 87b, 87c, 87d . . . ) that define the walls of the cone. The resonant frequency of the planar transducer is lower than the resonant frequency of the transducer segments. The planar, flat, circular transducer generates fixed frequency (5 KHz-1 MHz range) ultrasonic stimuli impulses for a predetermined period of time (10-20 seconds). Between the stimuli pulse periods, the transducer segments receive variable frequency ultrasonic pumping pulses. Preferably, the variable frequency ultrasonic pumping pulses lie in the 50 MHz-300 MHz range. The variable frequency ultrasonic pumping pulses are applied to opposed transducer segments. The transducer segments create beams that impinge on the skin at an oblique angle and create a pulsating wave. Further, the variable frequency ultrasonic pumping pulses are applied to opposing transducer segments in a rotating manner to create pulsating waves in the skin in a variety of directions. The stimuli pulses cause the planar transducer to produce an ultrasonic wave that excites the local nerves in the way that trauma (heat, force) excites the local nerves. The nerve excitation opens the epidermal/dermal junction membrane and the capillary endothelial cell joints. The variable frequency ultrasonic pumping pulses cause the transducer segments to produce ultrasonic waves in both the polymeric membrane and the skin. The ultrasonic waves pump the drug first through the polymeric membrane and then through, skin openings into the underlying blood vessels. The control electronics apply ultrasonic stimuli pulses to the skin by energizing the stimuli transducer at a first frequency, preferably lying in the 5 KHz-1 MHz range for a predetermined period of time (10-20 seconds). Between the stimuli pulse periods, the control electronics apply variable frequency ultrasonic pumping pulses to the skin by energizing the pumping transducer segments. Preferably, the frequency of the variable frequency ultrasonic pumping pulses lie in the 50 MHz-300 MHz range
U.S. Pat. No. 5,445,611, issued Aug. 29, 1995, titled xe2x80x9cEnhancement Of Transdermal Delivery With Ultrasound And Chemical Enhancersxe2x80x9d discloses a method of enhancing the permeability of the skin or mucosa to a biologically active permeant or drug is described utilizing ultrasound or ultrasound plus a chemical enhancer. If desired the ultrasound may be modulated by means of frequency modulation, amplitude modulation, phase modulation and/or combinations thereof. A frequency modulation from high to low develops a local pressure gradient directed into the body, thus permitting permeant to traverse the skin or mucosa. The enhanced delivery is preferably accomplished using a chemical enhancer, applying ultrasound optionally at a modulated frequency, amplitude, phase, or combinations thereof that further induces a local pressure gradient into the body. The method is also useful as a means for application of a tattoo by noninvasively delivering a pigment through the skin surface.
U.S. Pat. No. 5,614,502, issued Mar. 25, 1997, titled xe2x80x9cHigh Pressure Impulse Transient Drug Delivery for the Treatment of Proliferative Diseasesxe2x80x9d described the use of high pressure shock waves in combination with sub-toxic doses of compounds to treat proliferative diseases. A related patent, U.S. Pat. No. 5,658,892, issued Aug. 19, 1997, titled xe2x80x9cCompound Delivery Using High-Pressure Impulse Transientsxe2x80x9d discussed a method for increasing the delivery of a compound to the interior of a cell using a time-dependent pressure impulse. These two patents describe a technique that is intended to deliver a low number (typically less than 20) of fast rise-time (typically less than 35 ns), high pressure magnitude (typically 250-350 bars) acoustic waves to a collection of biological cells. Simultaneous administration of a therapeutic compound and the acoustic wave(s), enhance the delivery of the compound compared to normal passive diffusion. Means are discussed for creation of the acoustic shock waves and for selection of compound dosages based on the therapeutic index.
The invention is a means of locally producing high frequency acoustic waves, analogous to ultrasound, in vivo for the purpose of enhancing the delivery of therapeutic compounds into cells. This technique involves treating diseased or hyper-proliferative cells, such as those responsible for vascular hyperplasia leading to restenosis, and carcinomas, neoplasms, and sarcomas. The compounds delivered may be chemotherapeutic drugs (such as Taxol, 5-Aminoaleuvenic acid, anthracyclines), antibiotics, photodynamic drugs (such as psoralans, porphyrin derivatives), or gene therapies (RNA, DNA).
The therapeutic compounds are administered systemically, or preferably locally to the targeted site. Local delivery can be accomplished through a needle, cannula, or through a variety of vascular catheters, depending on the location of routes of access. Natural barriers may be used to limit diffusion of the compounds, or mechanical barriers such as a balloon catheter to dam a drug within a blood vessel.
To enhance the systemic or local delivery of the therapeutic compounds, high frequency acoustic waves are simultaneously delivered. The acoustic waves are generated locally near the target site, and preferably near the site of compound administration. The acoustic waves are produced via laser radiation interaction with an absorbing media and can be produced via thermoelastic expansion, thermodynamic vaporization, material ablation, or plasma formation. Ideally, a thermoelastic or thermodynamic mechanism is employed. For example, as a short burst of laser radiation is deposited into a strongly absorbing material, the material rapidly heats and expands, sending an acoustic wave into the surrounding media. The laser radiation may be delivered to a remote location via a fiber optic passed through a catheter or other cannula. Absorption of laser radiation may take place in native tissues or fluids, in applied absorbing dyes, in the therapeutic compound, or in a transducer placed near the target sight. An ultrasound effect may be produced by the delivery of laser pulses at high frequencies, greater than 100 Hz, and preferably greater than 1000 Hz. This ultrasound has the effect of temporarily, but non-toxically permeabilizing the membranes of local cells, increasing the diffusion of the therapeutic compound into the cells. In this way, the effectiveness of the compounds may be increased, allowing for decreased total body dosages, decreased side effects, and enabling new therapies.